Active ingredients: Doxorubicin
Caelyx 2 mg / ml concentrate for solution for infusion
Indications Why is Caelyx used? What is it for?
Caelyx is an anticancer agent.
Caelyx is used to treat breast cancer in patients at risk for heart problems. Caelyx is also used to treat ovarian cancer. It is used to kill cancer cells, reduce tumor size, delay tumor growth, and prolong its survival.
Caelyx is also used in combination with another medicine, bortezomib, to treat multiple myeloma, a cancer of the blood, in patients who have received at least one previous therapy.
Caelyx is also used to improve Kaposi's sarcoma, including flattening, turning pale and even reducing the size of the tumor. Other symptoms of Kaposi's sarcoma, such as swelling around the tumor, may also improve or disappear.
Caelyx contains a substance capable of interacting with cells in order to selectively kill cancer cells. The doxorubicin hydrochloride contained in Caelyx is enclosed in very small spheres, called pegylated liposomes, which facilitate the transport of the drug from the blood to the tumor tissue, avoiding its dispersion in healthy tissue.
Contraindications When Caelyx should not be used
Do not take Caelyx
- if you are allergic to doxorubicin hydrochloride or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before you take Caelyx
Tell your doctor about the following conditions:
- if you are being treated for heart or liver problems;
- if you have diabetes, as Caelyx contains sugar and your diabetes treatment may need to be adjusted accordingly;
- if you have Kaposi's sarcoma and your spleen has been removed;
- if you notice ulcers, discolouration or any discomfort in your mouth.
Children and adolescents
Caelyx should not be used in children and adolescents because it is not known how the medicine affects them.
Interactions Which drugs or foods may change the effect of Caelyx
Tell your doctor or pharmacist
- if you are taking or have recently taken any other medicines, including those obtained without a prescription,
- about all the treatments for the cancer he is following or has followed in the past, since "special attention is required for those treatments that reduce the number of white blood cells, as this can lead to a" further reduction in the number of blood cells whites. If you are not sure about the treatments you have received or the illnesses you have had, please talk to your doctor
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
As the active substance in Caelyx, doxorubicin hydrochloride, can cause changes in the unborn baby, it is important that you tell your doctor if you think you are pregnant. Women should avoid becoming pregnant if they or their partner are treated with Caelyx, and for six months after stopping treatment.
Since doxorubicin hydrochloride can be harmful to infants, women must stop breastfeeding before starting treatment with Caelyx. Experts recommend HIV-infected women not to breastfeed their children under any circumstances to prevent any transmission of HIV. .
Driving and using machines
Do not drive or use any tools or machines if you feel tired or sleepy following treatment with Caelyx.
Dose, Method and Time of Administration How to use Caelyx: Posology
Caelyx is a unique formulation. It must not be used interchangeably with other formulations of doxorubicin hydrochloride.
How much Caelyx is given
If you are being treated for breast or ovarian cancer, Caelyx will be given to you at a dose of 50 mg for every square meter of your body surface (based on your height and body weight). The dose is repeated every 4 weeks until the disease progresses and you are able to tolerate the treatment.
If you are being treated for multiple myeloma, and have already received at least one previous therapy, Caelyx will be given to you at a dose of 30 mg per square meter of your body surface (based on your height and body weight) via an intravenous infusion. 1 hour administered immediately following the bortezomib infusion on day 4 of the 3-week bortezomib treatment regimen. The dose will be repeated until you respond satisfactorily and tolerate treatment.
If you are being treated for Kaposi's sarcoma, Caelyx will be given at a dose of 20 mg for every square meter of your body surface (based on your height and weight). The dose is repeated every 2 or 3 weeks for 2 or 3 months; subsequently it will be repeated when it is necessary to maintain an improvement in his condition.
How Caelyx is given
Caelyx will be given to you by your doctor as a drip (infusion) into a vein. Depending on the dose and the indication, this will last from 30 minutes to more than one hour (ie 90 minutes).
Overdose What to do if you have taken too much Caelyx
Acute overdose worsens side effects such as sores in the mouth or a drop in white blood cells and blood platelets. Treatment will consist of the administration of antibiotics, the transfusion of platelets, the use of factors that stimulate the production of white blood cells, and the symptomatic treatment of sores in the mouth.
If you have any further questions on the use of Caelyx, ask your doctor or pharmacist.
Side Effects What are the side effects of Caelyx
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following reactions may occur during the infusion of Caelyx: flushing of the face, breathlessness, headache, chills, back pain, tightness in the chest and / or throat, sore throat, high or low blood pressure, increased heartbeat heart disease, facial swelling, fever, dizziness, nausea, digestive upset, itching, sudden skin redness and sweating.In very rare cases, seizures have occurred. Stinging pain or swelling at the injection site may also occur. If the drip makes you uncomfortable or painful while you are taking a dose of Caelyx, tell your doctor right away.
Contact your doctor immediately if:
- painful redness develops on the hands and feet,
- develop a painful sensation on the skin and / or blisters on the body or in the mouth,
- have heart problems,
- has sores in his mouth,
- have a rise in temperature or other signs of infection,
- have "sudden shortness of breath or sharp chest pain which may be worse with deep breathing or coughing,"
- have swelling, warmth or soft tissue sensitivity in the legs, sometimes with pain that gets worse if standing or walking.
Other side effects
In the period between infusions, the following effects may occur:
Very common (may affect more than 1 in 10 patients):
- redness, swelling and sores on the palms of the hands and soles of the feet. These effects have been observed frequently and are sometimes serious. In severe cases, these effects can interfere with some daily activities and can last up to 4 weeks or longer before resolving completely. The physician may at his discretion delay the initiation and / or reduce the dose of subsequent treatment (see Techniques to Prevent and Treat Hand and Foot Syndrome below);
- pain or sores in the mouth or throat, nausea, vomiting, diarrhea, constipation, loss of appetite, weight loss;
- decrease in the number of white blood cells, which can increase the chance of infections. Anemia (reduction in red blood cells) can cause you to feel tired and the decrease in blood platelets can increase the risk of bleeding. In rare cases, a low number of white blood cells can lead to serious infections. Because of the possible changes in blood levels. blood cells, regular blood monitoring is required In a clinical study in AIDS-KS patients comparing Caelyx with another treatment (bleomycin / vincristine), it was found that there may be an increased chance of some infections with Caelyx. However, contrary to the experience found in AIDS-KS patients, when Caelyx was compared to the standard treatment for advanced ovarian cancer (topotecan), the risk of infections was substantially lower in the Caelyx-treated patient group. The risk of low blood counts and infections was similarly low in breast cancer studies. Some of these effects may be related to the disease not Caelyx;
- general feeling of tiredness, weakness, pins and needles sensation or pain in the hands and feet;
- hair loss.
Common (may affect up to 1 in 10 patients):
- stomach pain;
- oral thrush (fungal infection of the mouth), sores in the nose, nosebleeds, cold sores, and inflammation of the tongue;
- liver function test values may either increase or decrease during treatment with Caelyx;
- drowsiness, dizziness, fainting, bone pain, chest pain, abnormal muscle tension, muscle pain, cramps or swelling in the lower limbs, general swelling, inflammation of the retina (the membrane of the eye stimulated by light), increased lacrimation, blurred vision, sensation of pins and needles or pain in the hands and feet;
- inflammation of the hair follicles, peeling of the skin, inflammation or rash, abnormal pigmentation (discoloration) of the skin and nail problems;
- heart problems, eg. irregular heartbeat, dilated blood vessels;
- fever, raised temperature or other signs of infection which may be related to the disease;
- breathing problems, i.e. difficulty in breathing or coughing which may be related to infections contracted as a result of the disease;
- not enough water in the body (dehydration), severe weight loss and muscle wasting, low levels of calcium, magnesium, potassium or sodium in the blood, high levels of potassium in the blood;
- inflammation of the esophagus (esophagitis), inflammation of the stomach lining, difficulty swallowing, dry mouth, flatulence, inflamed gums (gingivitis), changes in the sense of taste;
- inflammation of the vagina;
- pain when urinating;
- if you have previously developed skin reactions, ie pain, redness and dryness of the skin during radiation therapy, these may still occur during treatment with Caelyx;
- joint pain, reduced or abnormal sensation on stimulation, inflammation of the cornea, red eye, red scrotum may occur with the combination of Caelyx and bortezomib. When Caelyx is used alone, some of these effects are less likely, and some do not occur at all.
Uncommon (affects up to 1 in 100 patients)
- confusion;
- inflammation of the veins and blood clots in the veins which can block blood flow to the lungs and cause difficulty in breathing, chest pain and palpitations.
Very rare (affects up to 1 in 10,000 patients)
- severe skin reaction such as widespread peeling of the skin, blistering and erosion (ulcers) of the mucous membranes (Stevens-Johnson syndrome / toxic epidermal necrolysis);
- Mouth cancer may occur if Caelyx is taken for a long time (more than a year).
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Techniques to prevent and treat hand and foot syndrome include:
- whenever possible, immerse your hands and / or feet in a basin of cold water (eg while watching television, reading or listening to the radio);
- keep your hands and feet uncovered (no gloves, socks, etc.)
- stay in cool places;
- take cold baths during hot periods;
- avoid vigorous exercise that can cause foot trauma (eg jogging);
- avoid exposure of the skin to very hot water (eg hydromassage, sauna);
- avoid tight or high-heeled shoes.
Pyridoxine (Vitamin B6):
- vitamin B6 can be purchased without a prescription;
- take 50-150 mg per day starting at the first signs of redness or tingling.
Expiry and Retention
Keep Caelyx out of the sight and reach of children.
Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
After dilution:
- Chemical and physical in-use stability has been demonstrated for 24 hours at temperatures between 2 ° C and 8 ° C.
- From a microbiological point of view, the product should be used immediately. If not used immediately, storage times and methods of the diluted solution prior to its use are the responsibility of the user and should not exceed 24 hours when stored at temperatures between 2 ° C and 8 ° C. The vials partially used must be deleted.
Do not use this medicine after the expiry date which is stated on the label and carton.
Do not use this medicine if you notice any precipitate or other types of particles.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Caelyx contains
- The active ingredient is doxorubicin hydrochloride. One ml of Caelyx contains 2 mg of doxorubicin hydrochloride in a pegylated liposome formulation.
- The other ingredients are? - (2- [1,2-distearoyl-sn-glycerophosphoxy] ethylcarbamoyl) - omega - methoxy poly (oxyethylene) -40 sodium salt (MPEG-DSPE), fully hydrogenated soy phosphatidylcholine (HSPC), cholesterol, ammonium sulfate, sucrose, histidine, water for injections, hydrochloric acid and sodium hydroxide.
Caelyx 2 mg / ml concentrate for solution for infusion: vials capable of delivering a volume of 10 ml (20 mg) or 25 ml (50 mg).
What Caelyx looks like and contents of the pack
The solution for infusion is sterile, translucent and red. Caelyx is available in glass ampoules in single packs or containing 10 vials.
Not all pack sizes may be marketed.
The following information is intended for medical and healthcare professionals only:
The Caelyx solution should be handled with caution. Use of gloves is required. If Caelyx comes into contact with skin or mucous membranes, wash thoroughly with soap and water immediately. Caelyx should be handled and disposed of in accordance with the precautions indicated for other anticancer drugs.
Determine the dose of Caelyx to be administered (depending on the recommended dose and the patient's body surface area). Withdraw the correct volume of Caelyx using a sterile syringe. It is necessary to operate under strictly aseptic conditions, as Caelyx does not contain preservatives or bacteriostatic agents. Prior to administration, the correct dose of Caelyx must be diluted in 5% glucose solution (50 mg / ml) for intravenous infusion. For doses <90 mg dilute Caelyx in 250 ml and for doses? 90 mg dilute Caelyx in 500 ml.
To reduce the risk of infusion reactions, the initial dose should be administered at a rate not exceeding 1 mg / min. If no infusion reaction is observed, subsequent infusions of Caelyx can be administered over a period of 60 minutes.
In the breast cancer clinical trial program, a modification of the infusion was permitted in those patients who experienced a reaction following administration such as the following: 5% of the total dose was administered slowly during the first 15 minutes. tolerated without reaction, the infusion rate was doubled for the next 15 minutes. If tolerated, the infusion was completed over the next hour for a total injection time of 90 minutes.
If the patient exhibits early symptoms or signs of an infusion reaction, discontinue the infusion immediately, administer appropriate premedications (antihistamines and / or short-acting corticosteroids) and resume the infusion at a slower rate.
The use of diluents other than 5% glucose solution (50 mg / ml) for intravenous infusion or the presence of any bacteriostatic agent, such as benzyl alcohol, may cause precipitation of Caelyx.
It is recommended to connect the infusion line containing Caelyx to the "side inlet" of an intravenous infusion of 5% glucose (50 mg / ml). Infusion can be delivered through a peripheral vein. Do not use with inline filters.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CAELYX 2 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of Caelyx contains 2 mg of doxorubicin hydrochloride in a pegylated liposome formulation.
Caelyx consists of a liposomal formulation in which doxorubicin hydrochloride is encapsulated in liposomes on the surface of which methoxy polyethylene glycol (MPEG) is bound. This process, known as pegylation, protects liposomes from being recognized by the phagocytic mononuclear system (MPS), increasing their circulation time in the blood.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion
The suspension is sterile, translucent and red.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Caelyx is indicated:
- As monotherapy in patients with metastatic breast cancer, where there is an increased cardiac risk.
- For the treatment of advanced ovarian cancer in women who have failed first-line platinum-based chemotherapy.
- In combination with bortezomib for the treatment of progressive multiple myeloma in patients who have previously received at least one treatment and who have already undergone or cannot undergo bone marrow transplantation.
- For the treatment of AIDS-related Kaposi's sarcoma (KS-AIDS), in patients with low CD4 counts (CD4 3 lymphocytes) and diffuse mucocutaneous or visceral disease.
Caelyx can be used as first-line or second-line systemic chemotherapy in AIDS-KS patients with advanced disease or in patients intolerant to previous systemic combination chemotherapy treatment with at least two of the following substances: a vinca alkaloid , bleomycin and standard doxorubicin (or an "other anthracycline).
04.2 Posology and method of administration
Caelyx should only be administered under the supervision of an oncologist who specializes in the administration of cytotoxic agents.
Caelyx possesses unique pharmacokinetic properties; therefore it should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Breast cancer / Ovarian cancer :
Caelyx is administered intravenously at a dose of 50 mg / m2 once every 4 weeks until disease progression and the patient is able to tolerate the treatment.
Multiple myeloma : Caelyx is administered at a dose of 30 mg / m2 on day 4 of the 3-week bortezomib regimen, as a 1-hour intravenous infusion immediately following the bortezomib infusion. The bortezomib regimen consists of a dose of 1.3 mg / m2 on days 1, 4, 8 and 11 every 3 weeks. Therapy should be repeated as long as the patient demonstrates a satisfactory response and is able to tolerate the treatment. Day 4 dose of both drugs it may be delayed for up to 48 hours if medically necessary.Doses of bortezomib should be separated by at least 72 hours.
For intravenous doses.
For doses ≥ 90 mg: dilute Caelyx in 500 ml of 5% glucose solution (50 mg / ml) for intravenous infusion.
To minimize the risk of infusion-related reactions, the initial dose should be administered at a rate not exceeding 1 mg / minute. If no reactions are observed, subsequent infusions of Caelyx can be administered over 60 minutes.
In those patients who had a reaction following administration, a modification of the infusion was allowed such as the following:
5% of the total dose should be administered slowly over the first 15 minutes. If tolerated without reaction, the infusion rate can be doubled for the next 15 minutes. If tolerated, the infusion can be completed over the next hour for a total injection time of 90 minutes.
AIDS-related Kaposi's sarcoma :
Caelyx is administered intravenously at doses of 20 mg / m2 every two to three weeks. Avoid intervals of less than 10 days, as an accumulation of the product and an increase in toxicity cannot be excluded. To achieve a therapeutic response it is recommended that patients be treated for a period of two to three months. Continue treatment as needed to maintain therapeutic response.
The dose of Caelyx is diluted in 250 ml of 5% glucose solution (50 mg / ml) for intravenous infusion and administered by intravenous infusion over 30 minutes.
For all patients :
If the patient experiences early signs or symptoms of an infusion reaction (see sections 4.4 and 4.8), discontinue the infusion immediately, administer appropriate premedications (antihistamines and / or short-acting corticosteroids) and resume the infusion at a later time. slower speed.
Do not administer Caelyx as a bolus or undiluted solution. It is recommended that the infusion line containing Caelyx be connected to the side inlet of an intravenous infusion of 5% glucose (50 mg / mL) to further dilute the solution and minimize the risk of thrombosis and extravasation. The infusion can be administered through a peripheral vein. Do not use with in-line filters. Caelyx must not be administered intramuscularly or subcutaneously (see section 6.6).
For the management of adverse events such as palmar-plantar erythrodysaesthesia (PPE), stomatitis or haematological toxicity, the dose can be reduced or administration postponed. Guidelines for dose adjustment of Caelyx following these adverse events are provided in the tables below. The toxicity classification shown in these tables is based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC).
The tables for PPE (Table 1) and stomatitis (Table 2) provide the scheme followed for dose adjustment during clinical trials in the treatment of breast or ovarian cancer (modification of the recommended 4-week treatment course): if these toxicities occur in patients with KS-AIDS, the recommended treatment course of 2-3 weeks can be similarly modified.
The table for haematological toxicity (Table 3) provides the scheme followed for dose modification during clinical studies conducted only in patients with breast or ovarian cancer. For dose adjustment in AIDS-KS patients see section 4.8.
Caelyx Dose Adjustment Guidelines
For patients with multiple myeloma treated with Caelyx in combination with bortezomib who develop PPE or stomatitis, the dose of Caelyx should be adjusted as described in Tables 1 and 2 above. Table 4 below provides the scheme followed for other dose adjustments during the clinical trial in the treatment of patients with multiple myeloma who received Caelyx and bortezomib in combination therapy. For more information on bortezomib dosing and dose adjustments, see also the bortezomib Summary of Product Characteristics (SmPC).
* for more information on bortezomib dosing and dose adjustments see the bortezomib SmPC
Patients with hepatic insufficiency : the pharmacokinetics of Caelyx, determined in a small number of patients with elevated total bilirubin levels, do not differ from that of patients with normal total bilirubin; however until more information is available, the dosage of Caelyx in patients with hepatic insufficiency should be reduced based on experience from clinical studies in breast and ovarian cancer, as follows: at the start of therapy, if bilirubin is between 1.2 and 3.0 mg / dl, the first dose is reduced by 25%. If bilirubin is> 3.0 mg / dL, the first dose is reduced by 50%. If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose of the second cycle can be increased to the next level, that is, if the first dose was reduced by 25%, bring the full dose to the second cycle; if the first dose was reduced by 50%, increase to 75% of the full dose on the second cycle. If tolerated, the dosage can be increased to full dosage at subsequent cycles. Caelyx can be administered to patients with liver metastases and concomitant increases in bilirubin and liver enzymes up to 4 times the upper limit of the normal range. Prior to administration of Caelyx, evaluate liver function with conventional clinical laboratory tests such as ALT / AST, alkaline phosphatase and bilirubin.
Patients with renal insufficiency : As doxorubicin is metabolised by the liver and excreted in the bile, no dosage adjustment is required. Population pharmacokinetic data (in a tested range of creatinine clearance of 30-156 ml / min) demonstrate that the elimination of Caelyx is not affected by renal function. No pharmacokinetic data are available in patients with a creatinine clearance. less than 30ml / min.
Splenectomized KS-AIDS patients : As there is no experience with the use of Caelyx in patients undergoing splenectomy, its use is not recommended.
Pediatric patients : Experience in children is limited. Caelyx is not recommended in patients below 18 years of age.
Elderly patients : A population analysis shows that age in the range tested (21-75 years) does not significantly alter the pharmacokinetics of Caelyx.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
Caelyx should not be used for the treatment of AIDS-KS that can be effectively treated with local therapy or with systemic alpha-interferon.
04.4 Special warnings and appropriate precautions for use
Cardiac toxicity : It is recommended that all patients treated with Caelyx be routinely subjected to frequent electrocardiograms (ECG). Transient changes in the ECG pattern, such as flattening of the T wave, ST-segment sub-leveling, and benign arrhythmias are not considered binding signals for discontinuation of Caelyx therapy. However, the reduction of the QRS complex is considered the most indicative sign of cardiac toxicity. this alteration occurs, the decisive anthracycline myocardial toxicity test, i.e. endomyocardial biopsy, must be considered.
More specific methods of the electrocardiogram for the evaluation and control of cardiac function are the measurement of the ejection fraction of the left ventricle by means of echocardiography or, preferably, by means of multiple port arteriography (MUGA). These methods must be applied routinely prior to initiation of Caelyx therapy and should be repeated periodically during treatment. Evaluation of left ventricular function is considered essential prior to any additional administration of Caelyx that exceeds an allowable lifetime cumulative anthracycline dose of 450 mg / m2.
The evaluation tests and methods described above regarding cardiac monitoring during anthracycline therapy should be used in the following order: ECG monitoring, left ventricular ejection fraction measurement, endomyocardial biopsy. If a test result indicates a possible injury associated with Caelyx therapy, the benefit of continuing therapy must be carefully weighed against the risk of myocardial injury.
Treat patients with heart disease who need treatment with Caelyx only when the benefit outweighs the risk.
Caution should be exercised in patients with impaired cardiac function being treated with Caelyx.
Whenever cardiomyopathy is suspected, i.e. when the left ventricular ejection fraction has substantially decreased compared to the pre-treatment values and / or the left ventricular ejection fraction is lower than the relevant value from a prognostic point of view (eg.
Congestive heart failure due to cardiomyopathy can occur suddenly, even several weeks after discontinuation of treatment, without being preceded by changes in the electrocardiogram.
Caution should be exercised in patients treated with other anthracyclines. The total dose of doxorubicin hydrochloride must also take into account any previous (or concomitant) therapy with cardiotoxic compounds such as other anthracyclines / anthraquinones or eg. 5-fluorouracil. Cardiac toxicity can also occur with cumulative doses of anthracyclines below 450 mg / m2 in patients with previous mediastinal irradiation or in patients treated concomitantly with cyclophosphamide.
At the cardiac level, the safety profile of the recommended posology for both breast and ovarian cancer (50 mg / m2) is comparable to that of 20 mg / m2 in AIDS-KS patients (see section 4.8).
Myelosuppression : Many patients treated with Caelyx have underlying myelosuppression due to various factors such as pre-existing HIV infection or numerous concomitant or previous therapies, or tumors involving the bone marrow. In the pivotal study in ovarian cancer patients treated with 50 mg / m2, myelosuppression was generally mild to moderate, reversible and was not associated with episodes of neutropenic infection or sepsis. In addition, in a controlled clinical trial of Caelyx versus topotecan, the incidence of treatment-related sepsis was substantially lower in the Caelyx-treated ovarian cancer group than in the topotecan-treated group. A similar low incidence of myelosuppression was noted. in patients with metastatic breast cancer being treated with Caelyx in a first-line clinical trial. In contrast to the experience in breast or ovarian cancer patients, myelosuppression appears to be the dose-limiting adverse event in AIDS-KS patients (See section 4.8) Due to the potential for myeloablation, periodic blood tests should be performed frequently during Caelyx therapy, and at least before each dose of Caelyx.
Severe and persistent myelosuppression can lead to superinfection or haemorrhage.
In controlled clinical trials conducted in AIDS-KS patients compared to the bleomycin / vincristine regimen, opportunistic infections were apparently more frequent during treatment with Caelyx. Patients and doctors need to be aware of this increased incidence and act accordingly.
As with other DNA-damaging antineoplastic agents in patients receiving combination treatment with doxorubicin, secondary acute myeloid leukemias and myelodysplasias have been reported. Consequently, every patient treated with doxorubicin must be kept under haematological control.
Due to the difference in pharmacokinetic profile and dosing regimens, Caelyx should not be used interchangeably with other formulations of doxorubicin hydrochloride.
Reactions associated with the infusion : Severe and sometimes life-threatening infusion reactions may occur within minutes of starting the Caelyx infusion. These are characterized by allergic or anaphylactoid type reactions whose symptoms include asthma, flushing, rash itching, chest pain, fever, hypertension, tachycardia, itching, sweating, shortness of breath, facial edema, chills, back pain, tightness in the chest and throat and / or hypotension. Very rarely, convulsions have been observed as a reaction at the infusion (see section 4.8). Normally a temporary suspension of the infusion resolves these symptoms without further therapeutic intervention. However, drugs to treat these symptoms (for example, antihistamines, corticosteroids, epinephrine and anticonvulsants), as well as emergency equipment, must be available for immediate use. In most patients, treatment can be resumed after all symptoms have resolved, without relapse. Infusion reactions rarely recur after the first course of treatment. To minimize the risk of infusion reactions, the initial dose should be administered at an infusion rate not exceeding 1 mg / minute (see section 4.2).
Diabetic patients : It should be considered that each vial of Caelyx contains sucrose and is administered as a 5% glucose solution (50 mg / ml) for intravenous infusion.
For common adverse events requiring dose modification or discontinuation, see section 4.8.
04.5 Interactions with other medicinal products and other forms of interaction
No formal interaction studies between other medicinal products and Caelyx have been performed, although phase II combination studies with conventional chemotherapeutic agents have been conducted in patients with gynecological cancers. Caution should be exercised in concomitant use of drugs known to interact with standard doxorubicin hydrochloride. Caelyx, like other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anticancer therapies. In clinical trials in patients with solid tumors ( including breast and ovarian cancer) treated concomitantly with cyclophosphamide or taxanes, no new cumulative toxicities were found. In patients with AIDS, following the administration of standard doxorubicin hydrochloride, cases of exacerbation of haemorrhagic cystitis induced by cyclophosphamide and increased hepatotoxicity of 6-mercaptopurine. Caution is also required when concomitant administration of other cytotoxic agents, in particular myelotoxic agents, is required.
04.6 Pregnancy and breastfeeding
Pregnancy : Doxorubicin hydrochloride is thought to cause serious birth defects when administered during pregnancy. Therefore, Caelyx should not be used during pregnancy unless clearly necessary.
Women of childbearing potential should be advised to avoid pregnancy whether they or their partner are being treated with Caelyx or within six months following the end of Caelyx therapy (see section 5.3).
Feeding time : It is not known whether Caelyx is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions to the baby, the mother must stop breastfeeding before starting Caelyx. Health experts advise HIV-infected women not to breastfeed their children under any circumstances to prevent any transmission of HIV.
04.7 Effects on ability to drive and use machines
Caelyx has no or negligible influence on the ability to drive or use machines. However, clinical studies performed to date indicate that drowsiness and drowsiness are not frequently associated (
04.8 Undesirable effects
The most common undesirable effect reported in breast / ovarian cancer clinical trials (50 mg / m2 every 4 weeks) was palmar-plantar erythrodysaesthesia (PPE). The overall reported incidence of PPE was 44.0% - 46.1%. These effects were mostly mild, with severe (Grade III) cases reported in 17% - 19.5%. The incidence of reported life-threatening cases (Grade IV) was hands and feet at low temperatures, keeping them in cold water (soaking, bathing or swimming), avoiding excessive sources of heat / hot water and no constrictions (no socks , gloves or tight shoes) PPE appears to be mainly related to the dosing regimen and can be reduced by increasing the dose interval to 1-2 weeks (see section 4.2). However, in some patients, this reaction can be severe and debilitating and require discontinuation of treatment. Stomatitis / mucositis and nausea have also been commonly reported in subjects treated for breast / ovarian cancer, while in patients with AIDS-KS (20 mg / m2 every 2 weeks) myelosuppression (mainly leukopenia) was the most common undesirable effect (see KS-AIDS). Cases of PPE were reported in 16% of patients with multiple myeloma treated with Caelyx in combination with bortezomib. Grade 3 was reported in 5% of patients. No cases of grade 4 PPE were reported. The most frequently reported adverse events (related or therapy-emergent) with combination therapy (Caelyx + bortezomib) were (40%), diarrhea (35%), neutropenia (33%), thrombocytopenia (29%), vomiting (28%), fatigue (27%) and constipation (22%).
Breast cancer : In a phase III clinical study (I97-328), 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Caelyx (n = 254) at a dose of 50 mg / m2 every 4 weeks or doxorubicin (n = 255) at a dose of 60 mg / m2 every 3 weeks. The following common side effects were reported more often with doxorubicin than with Caelyx: nausea (53% vs. 37%; Grade III / IV 5% vs. 3%), vomiting (31% vs. 19%; Grade III / IV 4% vs. less than 1%), various manifestations of alopecia (66% vs. 20%), pronounced alopecia (54% vs. 7%) and neutropenia (10% vs. 4%; Grade III / IV 8% vs. . 2%).
Mucositis (23% vs. 13%; Grade III / IV 4% vs. 2%) and stomatitis (22% vs. 15%; Grade III / IV 5% vs. 2%) were reported more frequently with Caelyx than with doxorubicin. The mean duration of the most common serious events (Grade III / IV) for both groups was 30 days or less. See Table 5 for the full list of undesirable effects reported in patients treated with Caelyx.
The incidence of life-threatening (Grade IV) haematological effects was
Clinically significant laboratory abnormalities (Grades III and IV) were few in this group, with elevated total bilirubin levels, AST and ALT reported in 2.4%, 1.6% and
* palmar-plantar erythrodysaesthesia (hand-foot syndrome).
Ovarian cancer : 512 ovarian cancer patients (a subpopulation of 876 solid tumor patients) were treated in clinical trials with Caelyx at a dose of 50 mg / m2. See Table 6 for undesirable effects reported in patients treated with Caelyx.
* palmar-plantar erythrodysaesthesia (hand-foot syndrome).
Myelosuppression was mostly mild to moderate and manageable. Sepsis related to leukopenia was not observed frequently (
In a subpopulation of 410 ovarian cancer patients, clinically significant changes in laboratory parameters during clinical trials with Caelyx included increased total bilirubin (usually in patients with liver metastases) (5%) and serum levels of creatinine (5%). Increases in AST levels have been reported less frequently (
Solid tumor patients: In a larger cohort study of 929 solid tumor patients (including breast and ovarian cancer) treated mostly at a dose of 50 mg / m2 every 4 weeks, the safety profile and incidence of adverse events were comparable to those in patients treated in the pilot breast and ovarian cancer trials.
Multiple myeloma: In a phase III study, of the 646 multiple myeloma patients who had previously received at least one treatment, 318 were treated with Caelyx 30 mg / m2 administered as a 1 hour intravenous infusion on day 4 of bortezomib therapy. Bortezomib was administered at a dose of 1.3 mg / m2 on days 1, 4, 8 and 11 every three weeks in combination with Caelyx or as monotherapy. See Table 7 for undesirable effects reported in ≥ 5% of patients treated with Caelyx and bortezomib combination therapy.
Neutropenia, thrombocytopenia and anemia were the most commonly reported haematological undesirable effects with the combination of Caelyx and bortezomib and bortezomib alone. The incidence of grade 3 and 4 neutropenia was higher in the combination therapy group than in the combination therapy group. to the group treated in monotherapy (28% vs 14%). The incidence of grade 3 and 4 thrombocytopenia was higher for combination therapy than monotherapy (22% vs 14%). The incidence of anemia was comparable in the two groups (7% vs 5%).
Cases of stomatitis were reported more frequently in the combination group (16%) than in the monotherapy group (3%) and many of them were grade 2 or less. Grade 3 stomatitis was reported in 2% of patients on combination therapy No grade 4 stomatitis was reported.
Nausea and vomiting were reported more frequently in the combination group (40% and 28%) than in the monotherapy group (32% and 15%); the majority were in severity grade 1 and 2.
Discontinuation of treatment with one or both drugs due to undesirable effects occurred in 38% of patients. The most common side effects leading to discontinuation of bortezomib and Caelyx treatment included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopenia, decreased ejection fraction and fatigue.
* palmar-plantar erythrodysaesthesia (hand-foot syndrome).
** Grade 3 and 4 undesirable effects are based on adverse events of each severity with an "overall incidence ≥ 5% (see undesirable effects listed in the first column)
KS-AIDS : Clinical studies in AIDS-KS patients treated with Caelyx at a dosage of 20 mg / m2 indicate that the most frequent undesirable effect associated with the administration of Caelyx is myelosuppression which also occurs very commonly (approximately half of patients).
Leukopenia is the most frequently reported undesirable effect with Caelyx in this population; neutropenia, anemia and thrombocytopenia have been reported. These effects can occur early on in treatment. Haematological toxicity may require dose reduction or discontinuation or postponement of treatment. Temporarily withhold Caelyx treatment in patients when the absolute neutrophil count is 3 and / or the platelet count is 3. G-CSF (or GM-CSF) can be given as concomitant supportive therapy in subsequent cycles when the absolute count is of neutrophils is 3. Haematological toxicity for ovarian cancer patients is less severe than for AIDS-KS patients (see section on ovarian cancer patients above).
Respiratory side effects were commonly observed in clinical trials of Caelyx and may be related to opportunistic infections in AIDS patients. Opportunistic infections occurred in patients with KS after administration of Caelyx; such infections are frequent in patients with HIV-induced immune deficiency. The most common opportunistic infections observed in clinical trials were candidiasis, cytomegalovirus, herpes simplex, pneumonia Pneumocystis carinii and mycobacterium avium complex.
Undesirable effects observed in patients with KS-AIDS according to CIOMS III frequency categories (Very common (> 1/10); Common (> 1/100, 1 / 1,000,
Infections and infestations:
Common: oral moniliasis
Disorders of the blood and lymphatic system:
Very common: neutropenia, anemia, leukopenia
Common: thrombocytopenia
Metabolism and nutrition disorders:
Common: anorexia
Psychiatric disorders:
Uncommon: confusion
Nervous system disorders:
Common: dizziness
Uncommon: paraesthesia
Eye disorders:
Common: retinitis
Vascular disorders:
Common: vasodilation
Respiratory, thoracic and mediastinal disorders:
Common: dyspnoea
Gastrointestinal disorders:
Very common: nausea
Common: diarrhea, stomatitis, vomiting, mouth ulceration, abdominal pain, glossitis, constipation, nausea and vomiting
Skin and subcutaneous tissue disorders:
Common: alopecia, rash
Uncommon: palmar-plantar erythrodysaesthesia (PPE)
General disorders and administration site conditions:
Common: asthenia, fever, acute infusion associated reactions
Diagnostic tests:
Common: weight loss
Other less frequently encountered undesirable effects (anaphylactic reactions. A blister rash has rarely been reported in this population after marketing.
Clinically significant laboratory abnormalities appeared frequently (≥ 5%) and included elevations in alkaline phosphatase, AST, and bilirubin which were considered associated with the disease and not with Caelyx. Decreases in hemoglobin and platelets were found less frequently (HIV virus and not in Caelyx.
All patients Reactions associated with Caelyx infusion defined by the following Costart indices were reported in 100 of 929 patients (10.8%) with solid tumors: allergic reaction, anaphylactoid reaction, asthma, facial edema, hypotension, vasodilation, urticaria, pain back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, feeling dizzy, dyspnoea, pharyngitis, rash, itching, sweating, injection site reactions and drug interactions. Permanent discontinuation of treatment is rarely (2%) reported. Infusion reactions (12.4%) and treatment discontinuation cases (1.5%) were reported in the breast cancer program at a similar incidence. In patients with multiple myeloma treated with Caelyx and bortezomib, the associated reactions infusion were reported at a frequency of 3%. In patients with KS-AIDS, infusion-associated reactions have been characterized by flushing, shortness of breath, facial edema, headache, chills, back pain, chest and throat tightness and / or hypotension and can be expected. with an incidence of 5% - 10%. Very rarely, seizures as an infusion reaction have been observed. In all patients, infusion-related reactions occurred mainly during the first infusion. A temporary suspension of the infusion usually resolves these symptoms without the use of further therapy. In almost all patients, Caelyx treatment can be resumed after all symptoms have resolved without relapse. Infusion reactions rarely occur after the first course of treatment with Caelyx (see section 4.2).
Myelosuppression associated with anemia, thrombocytopenia, leukopenia and neutropenia, and rarely febrile-type neutropenia, has been reported in patients treated with Caelyx.
Stomatitis has occurred in patients treated with continuous infusions of conventional doxorubicin hydrochloride, and frequently in patients treated with Caelyx. Stomatitis did not interfere with patients' completion of therapy and generally did not require dosage adjustments unless it affected the patient's ability to feed. In this case the dose interval can be increased by 1-2 weeks or the dose reduced (see section 4.2).
Doxorubicin therapy at permissible cumulative lifetime doses> 450 mg / m2 or lower doses for patients with cardiac risk factors is associated with a higher incidence of congestive heart failure. Nine out of ten endomyocardial biopsies, performed in patients with KS-AIDS and treated with cumulative doses of Caelyx greater than 460 mg / m2, showed no anthracycline-induced cardiomyopathy.The recommended dose of Caelyx for AIDS-KS patients is 20 mg / m2 every two to three weeks. The cumulative dose at which cardiotoxicity is expected to become a risk for these AIDS-KS patients (> 400 mg / m2) would require over 20 courses of Caelyx therapy, which takes 40-60 weeks to administer.
Eight solid tumor patients treated with cumulative anthracycline doses of 509 mg / m2 - 1680 mg / m2 underwent endomyocardial biopsy. The Billingham cardiotoxicity range score was 0 - 1.5. These scores correspond to no or mild cardiac toxicity.
In a major Phase III vs doxorubicin study, 58/509 (11.4%) randomized subjects (10 treated with Caelyx at a dose of 50 mg / m2 / every 4 weeks compared with 48 patients treated with doxorubicin at a dose of 60 mg / m2 / every 3 weeks) met protocol-defined criteria for cardiac toxicity during treatment and / or follow-up. Cardiac toxicity was defined as a reduction of greater than or equal to 20 points from the value if the resting LVEF remained in the normal range or as a reduction greater than or equal to 10 points if the LVEF became abnormal (less than the lower limit of normal). None of the 10 Caelyx-treated subjects who had cardiac toxicity based on LVEF values developed characteristic signs and symptoms of CHF. In contrast, 10 of 48 doxorubicin-treated subjects who presented with cardiac toxicity based on LVEF values also developed signs and symptoms of CHF.
In patients with solid tumors, including a subpopulation of breast and ovarian cancer patients, treated with a dose of 50 mg / m2 / cycle with cumulative doses of anthracycline over the entire lifetime, i.e. up to 1,532 mg / m2, the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with 50 mg / m2 / cycle of Caelyx and monitored for left ventricular ejection fraction (LVEF) before treatment and at least once during follow-up via MUGA scan, 88 patients received a cumulative dose of anthracyclines> 400 mg / m2, level of exposure associated with an increased risk of cardiovascular toxicity with conventional doxorubicin. Of these 88 patients, only 13 (15%) reported at least one "clinically significant change in their LVEF, defined as an LVEF value of less than 45% or a decrease of at least 20 points from baseline. In addition, only 1 patient ( treated with a cumulative anthracycline dose of 944 mg / m2) discontinued treatment due to clinical symptoms of congestive heart failure.
As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasia have been reported in patients receiving combination treatment with doxorubicin. Consequently, every patient treated with doxorubicin must be kept under haematological control.
Caelyx is considered an irritant, although local necrosis following extravasation has been very rarely observed to date. Animal studies indicate that administration of liposomal formulation doxorubicin hydrochloride reduces the potential for extravasation injury. If there are signs and symptoms of extravasation (eg, stinging pain, erythema), stop the infusion immediately and resume it in a different vein. Applying ice to the extravasation site for about 30 minutes may help relieve the reaction. local. Caelyx must not be administered intramuscularly or subcutaneously.
Rarely, the recurrence of skin reactions from previous radiotherapy may occur with the administration of Caelyx.
Serious skin conditions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely since marketing of Caelyx.
Cases of venous thromboembolism, including thrombophlebitis, venous thrombosis and pulmonary embolism, have been observed uncommonly in patients treated with Caelyx. However, as cancer patients are at increased risk of developing thromboembolic disease, a causal relationship cannot be determined.
04.9 Overdose
Acute overdose of doxorubicin hydrochloride worsens the toxic effects of mucositis, leukopenia and thrombocytopenia. Treatment of acute overdose in severely myelosuppressed patients requires hospitalization, administration of antibiotics, transfusion of platelets and granulocytes, and symptomatic treatment of mucositis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code: L01DB.
The active substance in Caelyx is doxorubicin hydrochloride, a cytotoxic antibiotic from the anthracycline group obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumor activity of doxorubicin is not known. It is generally believed that the inhibition of DNA, RNA and protein synthesis is the main cause of the cytotoxic effect, probably due to the intercalation of anthracycline between the adjacent pairs of bases of the DNA double helix, preventing it from unwinding for replication.
A randomized phase III trial comparing Caelyx vs doxorubicin involved 509 patients with metastatic breast cancer. The protocol-specified goal of demonstrating non-inferiority of Caelyx to doxorubicin was met; the relative hazard ratio (HR) to progression-free survival (PFS) was 1.00 (95% CI for HR = 0.82-1.22) HR treatment for PFS when adjusted for prognostic variables corresponded to the PFS for the ITT population.
The primary analysis of cardiac toxicity showed that the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Caelyx than with doxorubicin (HR = 3.16, p 2, no cardiac events occurred with Caelyx.
A phase III comparative study of Caelyx versus topotecan was completed in 474 patients with epithelial ovarian cancer who failed first-line platinum-based chemotherapy. C "was an overall survival (OS) benefit of patients treated with Caelyx compared to those treated with topotecan, as indicated by the relative hazard ratio (HR) of 1.216 (95% CI; 1.000, 1.478), P = 0.050. The 1, 2, and 3-year survival rates were 56.3%, 34.7%, and 20.2% for Caelyx, respectively, compared to 54.0%, 23.6%, and 13.2% for Topotecan.
In the subgroup of patients with platinum-sensitive disease the difference was greater: HR of 1.432 (95% CI; 1.066, 1.923), p = 0.017. The 1, 2, and 3-year survival rates were 74.1%, 51.2%, and 28.4% for Caelyx, respectively, compared to 66.2%, 31.0%, and 17.5% for Topotecan.
Treatments were similar in the subgroup of patients with non-platinum-sensitive disease: HR of 1.069 (95% CI; 0.823, 1.387), p = 0.618. The 1, 2, and 3-year survival rates were 41.5%, 21.1%, and 13.8% for Caelyx, respectively, compared to 43.2%, 17.2%, and 9.5% for Topotecan.
In 646 multiple myeloma patients who had received at least one prior therapy and who had not progressed on anthracycline-based therapy, an open-label, multicenter, randomized, parallel-group, phase III clinical trial was conducted to compare tolerability and "Efficacy of Caelyx + bortezomib combination therapy versus bortezomib monotherapy. There was a significant improvement in the primary endpoint, time to progression (TTP), in patients treated with Caelyx + bortezomib combination therapy compared to patients treated with bortezomib alone as indicated by a risk reduction (RR) of 35% (95% CI; 21-47%), p
05.2 Pharmacokinetic properties
Caelyx is a long-circulating, pegylated liposomal formulation of doxorubicin hydrochloride. Pegylated liposomes contain surface bonded segments of the hydrophilic polymer methoxy polyethylene glycol (MPEG). These linear groups extend from the liposome surface creating a protective coating that reduces interactions between the two-layered lipid membrane and plasma components. This allows Caelyx liposomes to circulate in the blood for prolonged periods. The pegylated liposomes are small enough (average diameter of about 100 nm) to pass intact (by extravasation) through the fenestrated capillaries that supply the tumors. Evidence of penetration of pegylated liposomes from blood vessels and of entry and accumulation into tumors was found in mice with C-26 colon cancer and in transgenic mice with KS-like lesions. Pegylated liposomes are also characterized by a low permeability lipid matrix and an internal aqueous buffer system, which help maintain encapsulated doxorubicin hydrochloride while the liposome remains in circulation.
The plasma pharmacokinetics of Caelyx in humans differ significantly from those reported in the literature for standard preparations of doxorubicin hydrochloride. At the lowest doses (10 mg / m2 - 20 mg / m2) Caelyx is characterized by linear pharmacokinetics. between 10 mg / m2 and 60 mg / m2 Caelyx is characterized by non-linear pharmacokinetics. Standard doxorubicin hydrochloride exhibits significant tissue distribution (volume of distribution 700 to 1,100 l / m2) and rapid elimination clearance (24 to 73 l / h / m2). The pharmacokinetic profile of Caelyx indicates, on the other hand, that this product remains mainly confined within the plasma volume, and that the clearance of doxorubicin from the blood depends on the liposomal transporter. The availability of doxorubicin begins after the extravasation of the liposomes and their entry into the tissue compartment.
For equivalent doses, the plasma concentration and AUC values of Caelyx representing mainly doxorubicin hydrochloride in pegylated liposomes (containing 90% - 95% of the measured doxorubicin) are significantly higher than the values obtained with standard preparations of doxorubicin hydrochloride.
Caelyx must not be used interchangeably with other formulations of doxorubicin hydrochloride.
Population pharmacokinetics
The pharmacokinetics of Caelyx were evaluated in 120 patients from 10 different clinical studies using the population pharmacokinetic approach. The pharmacokinetics of Caelyx in the dose range of 10 mg / m2 to 60 mg / m2 are best described by a two-compartment, non-linear model with zero-order inputs and Michealis-Menten elimination. The mean intrinsic clearance of Caelyx was 0.030 L / h / m2 (range 0.008 to 0.152 L / h / m2) and the mean central volume of distribution was 1.93 L / m2 (range 0.96 to 3.85 l / m2) approximating the plasma volume. The apparent half-life ranged from 24 to 231 hours, with a mean of 73.9 hours.
Breast cancer patients
The pharmacokinetics of Caelyx determined in 18 breast cancer patients were similar to the pharmacokinetics determined in a larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 L / h / m2 (range of 0.008-0.027 L / h / m2), the mean volume of distribution was 1.46 L / m2 (range 1.10-1.64 L / m2) . The mean apparent half-life was 71.5 hours (range of 45.2-98.5 hours).
Ovarian cancer patients
The pharmacokinetics of Caelyx evaluated in 11 ovarian cancer patients were similar to that determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.021 L / h / m2 (range 0.009 to 0.041 L / h / m2) and the mean central volume of distribution was 1.95 L / m2 (range 1.67 to 2 , 40 l / m2). The mean apparent half-life was 75.0 hours (range 36.1 to 125 hours).
Patients with KS-AIDS
The plasma pharmacokinetics of Caelyx were evaluated in 23 KS patients who were given single doses of 20 mg / m2 by infusion over 30 minutes. The pharmacokinetic parameters of Caelyx (primarily representing doxorubicin hydrochloride in pegylated liposomes and low levels of unencapsulated doxorubicin hydrochloride) were measured following administration of 20 mg / m2 and are presented in Table 8.
Table 8. Pharmacokinetic parameters in AIDS-KS patients treated with Caelyx
* Measured at the end of a 30 minute infusion
05.3 Preclinical safety data
The toxicological profile of Caelyx in repeated dosing studies in animals is very similar to that reported for long-term infusions of standard doxorubicin hydrochloride in humans. With Caelyx, encapsulation of doxorubicin hydrochloride in pegylated liposomes results in the following effects. different intensity.
Cardiotoxicity : Studies conducted in rabbits have shown that the cardiotoxicity of Caelyx is reduced compared to that induced by conventional formulations of doxorubicin hydrochloride.
Skin toxicity : In studies conducted by repeated administration of Caelyx in rats and dogs, severe inflammation of the dermis and ulcer formations were observed at clinically relevant doses. In the dog study the incidence and severity of these lesions were reduced by lowering the dose or by prolonging the intervals between doses. Similar dermal lesions, which are described as palmar-plantar erythrodysaesthesia, have also been observed in patients after intravenous infusion at long term (see section 4.8).
Anaphylactoid response : An acute response characterized by hypotension, pale mucous membranes, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed after administration of pegylated liposomes (placebo) during repeated dose toxicology studies in dogs. A similar but less severe response was seen in dogs treated with Caelyx and standard doxorubicin.
The hypotensive response was reduced in intensity with antihistamine-based pretreatment. However, the response did not endanger the dogs who recovered quickly after discontinuing treatment.
Local toxicity : Subcutaneous tolerability studies show that Caelyx, compared to standard doxorubicin hydrochloride, causes local irritation or milder tissue damage after possible extravasation.
Mutagenicity and carcinogenicity : although no studies have been conducted in this regard, doxorubicin hydrochloride, a pharmacologically active component of Caelyx, is mutagenic and carcinogenic. Placebo pegylated liposomes are neither mutagenic nor genotoxic.
Reproductive toxicity : Caelyx causes mild to moderate ovarian and testicular atrophy after a single dose of 36 mg / kg in mice. Decreased testicular weight and hypospermia were present in rats treated with repeated doses ≥ 0.25 mg / kg / day and in dogs, widespread degeneration of the seminiferous tubules and a marked decline in spermatogenesis (see section 4.6).
Nephrotoxicity : A study showed that a "single intravenous administration of Caelyx of more than double the clinical dose results in renal toxicity in monkeys. Renal toxicity has been observed even with single lower dose doses of doxorubicin HCl in rats and rabbits. Since an evaluation. global patient post-marketing safety data of Caelyx did not suggest a significant trend of Caelyx in terms of nephrotoxicity, the data observed in monkeys may not be relevant for patient risk assessment.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
? - (2- [1,2-distearoyl-sn-glycerophosphoxy] ethylcarbamoyl) -? - methoxy poly (oxyethylene) -40 sodium salt (MPEG-DSPE)
fully hydrogenated soy phosphatidylcholine (HSPC)
cholesterol
ammonium sulfate
sucrose
histidine
water for injections
hydrochloric acid
sodium hydroxide
06.2 Incompatibility
This medicinal product must not be mixed with other products except those mentioned in section 6.6.
06.3 Period of validity
20 months
After dilution:
- Chemical and physical in-use stability has been demonstrated for 24 hours at temperatures between 2 ° C and 8 ° C.
- From a microbiological point of view, the product should be used immediately. If not used immediately, storage times and methods of the diluted solution prior to its use are the responsibility of the user and should not exceed 24 hours when stored at temperatures between 2 ° C and 8 ° C.
- Partially used vials should be discarded.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C-8 ° C). Do not freeze.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Type I glass vial with siliconised gray bromobutyl stopper and aluminum seal containing a volume capable of delivering 10 ml (20 mg) or 25 ml (50 mg).
Caelyx is supplied in single packs or packs of ten vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Do not use the product if precipitate or other types of particles are present.
The Caelyx solution should be handled with caution. Use of gloves is required. If Caelyx comes into contact with skin or mucous membranes, wash thoroughly with soap and water immediately. Caelyx must be handled and disposed of in accordance with normal precautions used for other anticancer drugs in accordance with local regulations .
Determine the dose of Caelyx to be administered (depending on the recommended dose and the patient's body surface area). Withdraw the correct volume of Caelyx using a sterile syringe. It is necessary to operate under strictly aseptic conditions, as Caelyx does not contain preservatives or bacteriostatic agents. Prior to administration, the correct dose of Caelyx must be diluted in 5% glucose solution (50 mg / ml) for intravenous infusion. For doses
The use of diluents other than 5% glucose solution (50 mg / ml) for intravenous infusion or the presence of any bacteriostatic agent, such as benzyl alcohol, may cause precipitation of Caelyx.
It is recommended that the infusion line containing Caelyx be connected to the side inlet of an intravenous infusion of 5% glucose (50 mg / ml). The infusion can be administered through a peripheral vein. Do not use with inline filters.
07.0 MARKETING AUTHORIZATION HOLDER
Janssen Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/96/011/001
033308014
EU / 1/96/011/002
033308026
EU / 1/96/011/003
033308038
EU / 1/96/011/004
033308040
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 21 June 1996
Date of last renewal: 19 May 2006
10.0 DATE OF REVISION OF THE TEXT
November 2010
